P-glycoprotein mediates resistance to histidine kinase inhibitors

Sonia Arora, Jin-Ming Yang, Ryutaro Utsumi, Tadashi Okamoto, Takashi Kitayama, William N. Hait

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Histidine kinase inhibitors are being developed as a new class of antimicrobial drugs. We recently demonstrated the activity of a class of histidine kinase inhibitors against a mammalian enzyme, elongation factor-2 kinase (eEF-2K), and the effect of these compounds on cancer cell viability (Arora et al., 2003). To further characterize these compounds, we studied their interaction with ATP-binding cassette transporters, which are known to mediate resistance to a variety of chemotherapeutic agents. The 24 compounds studied belong to three structural series of derivatives of 2-methylimidazolium iodide. We focused this work on a representative compound (NH125) because we found it to be most potent against both histidine kinase and eEF-2K among the series. Cell lines that expressed P-glycoprotein (P-gp) were 2- to 5-fold resistant to NH125. NH125 increased accumulation of P-gp substrates such as paclitaxel and doxorubicin but had no effect on the accumulation of non-P-gp substrates. P-gp modulators verapamil and trans-flupenthixol and MDR1-targeted siRNA increased sensitivity of multidrug-resistant cell lines to NH125. The presence of a benzyl group on the N-3 position of the 2-methylimidazolium iodide was important for the interaction with P-gp. C6-NH, an NH125-resistant cell line, markedly overexpressed P-gp compared with the parental cell line. In animal models, we found that NH125 increased by 129% the survival of sensitive P388 cells bearing mice but had no effect on mice harboring the resistant cell line. These observations indicate that certain histidine kinase inhibitors are substrates for P-gp and hence an important consideration in development of these agents as potential antimicrobial and anticancer agents.

Original languageEnglish (US)
Pages (from-to)460-467
Number of pages8
JournalMolecular Pharmacology
Volume66
Issue number3
StatePublished - Sep 2004

Fingerprint

P-Glycoprotein
Elongation Factor 2 Kinase
Cell Line
Iodides
Flupenthixol
ATP-Binding Cassette Transporters
Enzymes
Verapamil
Anti-Infective Agents
Paclitaxel
Antineoplastic Agents
Doxorubicin
Small Interfering RNA
Cell Survival
Glycoproteins
Animal Models
Histidine Kinase
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

Arora, S., Yang, J-M., Utsumi, R., Okamoto, T., Kitayama, T., & Hait, W. N. (2004). P-glycoprotein mediates resistance to histidine kinase inhibitors. Molecular Pharmacology, 66(3), 460-467.
Arora, Sonia ; Yang, Jin-Ming ; Utsumi, Ryutaro ; Okamoto, Tadashi ; Kitayama, Takashi ; Hait, William N. / P-glycoprotein mediates resistance to histidine kinase inhibitors. In: Molecular Pharmacology. 2004 ; Vol. 66, No. 3. pp. 460-467.
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Arora, S, Yang, J-M, Utsumi, R, Okamoto, T, Kitayama, T & Hait, WN 2004, 'P-glycoprotein mediates resistance to histidine kinase inhibitors', Molecular Pharmacology, vol. 66, no. 3, pp. 460-467.

P-glycoprotein mediates resistance to histidine kinase inhibitors. / Arora, Sonia; Yang, Jin-Ming; Utsumi, Ryutaro; Okamoto, Tadashi; Kitayama, Takashi; Hait, William N.

In: Molecular Pharmacology, Vol. 66, No. 3, 09.2004, p. 460-467.

Research output: Contribution to journalArticle

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Arora S, Yang J-M, Utsumi R, Okamoto T, Kitayama T, Hait WN. P-glycoprotein mediates resistance to histidine kinase inhibitors. Molecular Pharmacology. 2004 Sep;66(3):460-467.